Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9](I)[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][C@H:33]([CH3:35])[O:32][C@H:31]([CH3:36])[CH2:30]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1.[CH3:37][N:38]([CH3:45])[C:39]([NH:41][CH2:42][C:43]#[CH:44])=[O:40].CN(C=O)C>C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:10]=[C:9]([C:44]#[C:43][CH2:42][NH:41][C:39](=[O:40])[N:38]([CH3:45])[CH3:37])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][C@H:33]([CH3:35])[O:32][C@H:31]([CH3:36])[CH2:30]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1
Reactant: C#CCNC(=O)N(C)C
Reactant: COc1cc2c(Nc3c(Cl)cc(I)c4c3OCO4)ncnc2cc1OCCCN1C[C@@H](C)O[C@@H](C)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3c(Cl)cc(C#CCNC(=O)N(C)C)c4c3OCO4)ncnc2cc1OCCCN1C[C@@H](C)O[C@@H](C)C1
Reaction time: 1 h
Yield: 84.4 %

Procedure:
N-(5-Chloro-7-iodo-1,3-benzodioxol-4-yl)-7-[3-(cis-2,6-dimethylmorpholin-4-yl)propoxy]-6-methoxyquinazolin-4-amine (250 mg, 0.40 mmol) and N,N-dimethyl-N′-prop-2-yn-1-ylurea (100 mg, 0.79 mmol) in ethyl acetate (8 ml) stirred at room temperature, under an atmosphere of nitrogen, and treated with bis(triphenylphosphine)palladium(II) dichloride (28 mg, 10 mol %) followed by copper(I) iodide (8 mg, 10 mol %) and diisopropylamnine (81 mg, 0.81 mmol). The reaction was stirred 1 hr then DMF (4 ml) added and the reaction stirred for a further 1 hr. The resulting orange solution was evaporated in vacuo then treated with dilute aqueous sodium bicarbonate solution and extracted with dichloromethane. The extract was dried over magnesium sulphate and evaporated to an orange oil. Purification was by column chromatography on silica using increasing concentrations of methanolic ammonia in dichloromethane as eluent gave the title compound (211 mg, 85%) as a pale orange solid;
Reaction SMILES: CC(C)C[O:4][C:5](=[O:26])[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH:14]2[CH2:18][NH:17][C:16](=[C:19]=[S:20])[CH:15]2[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:8][CH:7]=1>FC(F)(F)C(O)=O>[C:19](=[C:16]1[CH:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:14]([CH2:13][CH2:12][C:9]2[CH:8]=[CH:7][C:6]([C:5]([OH:26])=[O:4])=[CH:11][CH:10]=2)[CH2:18][NH:17]1)=[S:20]
Reactant: CCOC(=O)C1C(=C=S)NCC1CCc1ccc(C(=O)OCC(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1C(=C=S)NCC1CCc1ccc(C(=O)O)cc1
Temperature: 25 °C
Yield: 104.6 %

Procedure:
A mixture of 4.17 grams (11.1 mmol) of 4-(2-[2-thiocarbonyl-3-carboethoxypyrrolidin-4-yl]ethyl)benzoic acid 2,2-dimethylethyl ester and 20 ml of trifluoroacetic acid was stirred at room temperature until a clear solution was obtained plus an additional 5 minutes. Next, the resulting mixture was concentrated in a rotary evaporator and the residue therefrom was dissolved in 10 ml of methanol. This new solution was carefully added to a suspension of 2 grams of NaHCO3 in saturated NaHCO3 solution. The pH was adjusted to 5.7 with acetic acid and the resulting mixture extracted with 5×20 ml of ethyl acetate. The combined extracts were dried (MgSO4) and then concentrated to give 3.87 grams (109% crude yield) of 4-(2-(2-thiocarbonyl-3-carboethoxypyrrolidin-4-yl)ethyl)benzoic acid as a foam which was sufficiently pure for use in Example 8. Crystalline 4-(2-(2-thiocarbonyl-3-carboethoxypyrrolidin-4-yl)ethyl)benzoic acid was obtained from chloroform. Selected data: mp 145° -148° C.; 1H NMR (DMSO-d6) δ10.39 (s, 1H), 7.80 (d, J=8.1 Hz, 2H), 7.24 (d, J=8.1 Hz, 2H), 4.06 (q, J=7.1 Hz, 2H), 3.64 (dd, J =10.9, 8.9 Hz, 1H), 3.46 (d, J=8.5 Hz, 1H), 3.20 (dd, J =10.9, 8.0 Hz, 1H), 2.64 (q, J=8.0 Hz, 1H), 2.54 (t, J=7.4 Hz, 2H), 1.70 (m, 2H), 1.12 (t, J=7.1 Hz, 3H); 13C NMR (DMSO-d6) δ198.6, 169.5, 167.0, 146.2, 129.1, 128.6, 128.1, 65.0, 60.4, 52.9, 40.8, 33.5, 32.6, 13.7; IR (CHCl3) 3410, 2985, 1732, 1694, 1517 cm-1 ; UV (EtOH) 236 nm (ε14 900), 271 (15 600); MS(FD) m/z 321 (M+). Anal. Calcd for C16H19NO4S: C, 59.79; H, 5.96; N, 4.36. Found: C, 59.77; H, 6.00; N, 4.37.
Reaction SMILES: [CH:1]([C:3]1([CH3:17])[C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH3:16])[C:7]=2[S:6][CH2:5][CH2:4]1)=O.[CH3:18][NH2:19]>C1C=CC=CC=1.CO>[CH3:17][C:3]1([CH:1]=[N:19][CH3:18])[C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH3:16])[C:7]=2[S:6][CH2:5][CH2:4]1
Reactant: CN
Reactant: Cn1c2c(c3ccccc31)C(C)(C=O)CCS2
Solvent: c1ccccc1
Solvent: CO
Product: CN=CC1(C)CCSc2c1c1ccccc1n2C
Reaction time: 2 h

Procedure:
To a solution of the product (2.0 g) of the above (1) in benzene (20 ml) is added a 30% solution (14 ml) of methylamine in methanol. The solution is stirred for 2 hours and evaporated to give 4,9-dimethyl-4-methyliminomethyl-2,3,4,9-tetrahydrothiopyrano[2,3-b]indole (IR: νmaxCHCl3 1660 cm-1). The product is dissolved in methanol (20 ml) and sodium borohydride (930 mg) is added thereto on ice bath. The mixture is stirred at room temperature for 1 hour and evaporated to remove the solvent. The residue is extracted with ether after addition of some pieces of ice and a 10% aqueous solution of sodium hydroxide. The ethereal extract is again extracted with hydrochloric acid. The extract is made alkaline with an aqueous solution of sodium hydroxide and extracted with ether. The extract is washed with a saline solution, dried and evaporated to give an oil. Crystallization from hydrochloric acid--ethanol gives the hydrochloride (2.06 g) of the title compound melting at 274° C. (decomp.). Yield: 86%.
Reaction SMILES: S1C=CC2C(=O)C=CC=CC1=2.[S:12]1[CH:16]=[CH:15][C:14]2[CH:17]([NH:22]C=O)[CH2:18][CH2:19][CH2:20][CH2:21][C:13]1=2.[ClH:25]>>[ClH:25].[S:12]1[CH:16]=[CH:15][C:14]2[CH:17]([NH2:22])[CH2:18][CH2:19][CH2:20][CH2:21][C:13]1=2
Reactant: O=CNC1CCCCc2sccc21
Agent: Cl
Agent: O=c1ccccc2sccc12
Product: NC1CCCCc2sccc21

Procedure:
5,6,7,8-Tetrahydro=4H-cyclohepta[b]thiophen-4-one is converted to N-(5,6,7,8-tetrahydro-4H-cyclohepta[b]thien-4-yl)formamide, m.p. 164°-166° C., by the method of Xloetzel et al., Journal of Organic Chemistry 18, 1511 (1953). Hydrolysis of the formanide is accomplished by refluxing for one hour in 1 N hydrochloric acid and evaporating to dryness to afford 5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophen-4-amine hydrochloride, m.p. 233°-236° C. dec. The amine hydrochloride is then allowed to react with methyl isocyanate in dry tetrahydrofuran as solvent in the presence of a stoichiometric equivalent of triethylamine to afford 1-methyl-3-(5,6,7,8-tetrahydro-4H-cyclohepta[b]thien-4-yl)urea, m.p. 220°-222° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[CH3:17][C:18]1[S:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1>>[CH3:23][C:21]1[S:22][C:18]([CH:17]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[NH:11][C:10]2=[O:16])=[CH:19][CH:20]=1
Reactant: Cc1ccc(C=O)s1
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Product: Cc1ccc(C=C2C(=O)Nc3cccc(-c4ccncc4)c32)s1

Procedure:
4-Pyridin-4-yl-1,3-dihydroindol-2-one was condensed with 5-methylthiophene-2-carbaldehyde to give the title compound.
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[C:7](=[C:8]([O:16][CH3:17])[CH:9]=[C:10]([C:13]([OH:15])=O)[CH:11]=3)[C:6]([CH3:18])=[CH:5]2)[CH2:3][CH2:2]1.Cl.Cl.[Br:21][C:22]1[CH:23]=[C:24]([C:28]2[CH:29]=[C:30]3[C:40](=[CH:41][CH:42]=2)[O:39][C:33]2([CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:32][C:31]3=[O:43])[CH:25]=[N:26][CH:27]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C(OCC)(=O)C.CN(C=O)C.C(N(CC)CC)C>[Br:21][C:22]1[CH:23]=[C:24]([C:28]2[CH:29]=[C:30]3[C:40](=[CH:41][CH:42]=2)[O:39][C:33]2([CH2:34][CH2:35][N:36]([C:13]([C:10]4[CH:11]=[C:12]5[C:7]([C:6]([CH3:18])=[CH:5][N:4]5[CH:1]5[CH2:2][CH2:3]5)=[C:8]([O:16][CH3:17])[CH:9]=4)=[O:15])[CH2:37][CH2:38]2)[CH2:32][C:31]3=[O:43])[CH:25]=[N:26][CH:27]=1
Reactant: O=C1CC2(CCNCC2)Oc2ccc(-c3cncc(Br)c3)cc21
Reactant: COc1cc(C(=O)O)cc2c1c(C)cn2C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4cncc(Br)c4)ccc2O3)cc2c1c(C)cn2C1CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Triethylamine (0.33 mL) was added to a DMF (7.5 mL) solution of 1-cyclopropyl-4-methoxy-3-methyl-1H-indole-6-carboxylic acid (147 mg), 6-(5-bromo-3-pyridinyl)spiro-[chroman-2,4′-piperidin]-4-one dihydrochloride (268 mg), WSC hydrochloride (164 mg) and HOBT (110 mg), and stirred at r.t. for 5 h. This reaction mixture was diluted with ethyl acetate, then washed with water, aqueous saturated sodium bicarbonate and saturated saline water in that order, and dried with sodium sulfate. This was filtered, concentrated, and purified through silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound as a colorless amorphous substance. 1H-NMR (400 MHz, DMSO-d6) δ: 8.86 (1H, d, J=2.0 Hz), 8.66 (1H, d, J=2.0 Hz), 8.36 (1H, t, J=2.0 Hz), 8.05-7.99 (2H, m), 7.24 (1H, d, J=8.6 Hz), 7.13 (1H, s), 7.00 (1H, s), 6.50 (1H, s), 4.40-4.08 (1H, br m), 3.83 (3H, s), 3.78-3.22 (4H, br m), 2.94 (2H, s), 2.31 (3H, s), 2.04-1.75 (4H, br m), 1.03-0.97 (2H, m), 0.89-0.84 (2H, m); MS [M+H]+=600, 602.
Reaction SMILES: Br[C:2]1[C:3]([F:21])=[C:4]([F:20])[C:5]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(N(CC)C(C)C)(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH3:73][O:74][C:75]1[CH:80]=[CH:79][C:78]([CH2:81][SH:82])=[CH:77][CH:76]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:20][C:4]1[C:5]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])=[C:6]([CH:11]=[C:2]([S:82][CH2:81][C:78]2[CH:79]=[CH:80][C:75]([O:74][CH3:73])=[CH:76][CH:77]=2)[C:3]=1[F:21])[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)c(F)c(F)c1Nc1ccccc1Cl
Reactant: COc1ccc(CS)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(SCc2ccc(OC)cc2)c(F)c(F)c1Nc1ccccc1Cl
Temperature: 100 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
To a solution of methyl 5-bromo-3,4-difluoro-2-((2-chlorophenyl)amino)benzoate (22.84 g, 60.65 mmol) in anhydrous 1,4-dioxane (200 mL) was added N,N-diisopropylethylamine (15.68 g, 121.30 mmol). Then Pd2(dba)3 (2.78 g, 3.03 mmol) followed by Xantphos (3.51 g, 6.06 mmol) and 4-methoxy-α-toluenethiol (10.27 g, 66.72 mmol) was added under nitrogen atmosphere. The mixture was stirred overnight at 100° C. under N2 atmosphere and then allowed to warm to ambient temperature. The insoluble matter was filtered off and the filter cake was washed ethyl acetate. The filtrate was diluted with water (300 mL) and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with water (100 mL) and brine (100 mL) sequentially, dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 50:1, v/v) to give the desired product (pale yellow solid, 24.18 g, 88.6% yield). 1H NMR (400 MHz, CDCl3): δ 9.14 (s, 1H), 7.77 (dd, 1H), 7.41 (dd, 1H), 7.24 (m, 3H), 7.19 (m, 1H), 7.01 (m, 1H), 6.88 (m, 2H), 4.02 (s, 2H), 3.92 (s, 3H), 3.81 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:15][C:14]2[C:13](=O)[C:12]3[C:11]([C:17]([O-])=[O:18])=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3]1.O.[NH2:22][NH2:23].C(O)(=O)C.C([O-])(O)=O.[Na+]>CC(N(C)C)=O>[CH3:1][C:2]1([CH3:20])[CH2:3][CH2:4][C:5]2[NH:6][C:7]3[C:12]4=[C:11]([C:17](=[O:18])[NH:22][N:23]=[C:13]4[C:14]=2[CH2:15]1)[CH:10]=[CH:9][CH:8]=3
Reactant: NN
Reactant: CC1(C)CCc2[nH]c3cccc(C(=O)[O-])c3c(=O)c2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)CCC2=C(C1)c1n[nH]c(=O)c3cccc(c13)N2
Temperature: 130 °C
Reaction time: 4 h
Yield: 49 %

Procedure:
A solution of 7,7-dimethyl-9-oxo-5,6,7,8,9,10-hexahydroacridine-1-carboxylate (3.3 g, 11.6 mmol) and hydrazine hydrate (15 mL) in DMA (22 mL) was heated at 110° C. for 1.5 h, acetic acid (30 mL) was added and the mixture was stirred at 130° C. for another 4 hours. The reaction mixture was cooled to room temperature, and aqueous NaHCO3 (80 ml) was added to the mixture, filtered. And the filtered cake was washed with water (50 mL) and methanol (30 mL) alternatively multiple times. The solvent was removed in vacuo to give 10,10-Dimethyl-8,9,10,11-tetrahydro-2H-pyridazino[5,4,3-kl]acridin-3(7H)-one as a yellow solid (1.50 g, 49%). 1H NMR (DMSO-d6) δ 11.71 (s, 1H), 10.36 (s, 1H), 7.59-7.63 (m, 1H), 7.42-7.44 (m, 1H), 7.25-7.27 (m, 1H), 2.49-2.52 (m, 2H), 2.10 (s, 2H), 1.55 (m, 2H), and 1.00 (s, 6H). MS (ESI) m/e [M+1]+268.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>CN(C=O)C.O>[CH2:2]([O:9][C:10]([CH:12]1[CH2:17][CH2:16][N:15]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:14][CH2:13]1)=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(OCc1ccccc1)C1CCNCC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)N1CCC(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
Piperidine-4-carboxylic acid benzyl ester, hydrochloride salt (1 g, 3.9 mmol, 1 e.) from step 3, was dissolved in DMF (15 ml), Triethylamine (0.55 ml, 4 mmol, 1 eq.) and methanesulfonylchloride were added. The mixture was stirred for 1 h at room temperature, then was poured in water (20 ml). The acqueous solution was extracted with Ethyl Acetate (90 ml) and the organic layer was dried over anhydrous sodium sulfate, evaporated under reduced pressure to give a colourless oil. Yield 78%, 0.9 g.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.[CH2:24]([NH:28][CH:29]([CH2:34][CH2:35][S:36][CH3:37])[C:30]([O:32][CH3:33])=[O:31])[CH:25]([CH3:27])[CH3:26].O>ClCCl>[CH2:24]([N:28]([S:14]([C:11]1[CH:12]=[CH:13][C:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:9][CH:10]=1)(=[O:16])=[O:15])[CH:29]([CH2:34][CH2:35][S:36][CH3:37])[C:30]([O:32][CH3:33])=[O:31])[CH:25]([CH3:27])[CH3:26]
Reactant: COC(=O)C(CCSC)NCC(C)C
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)C(CCSC)N(CC(C)C)S(=O)(=O)c1ccc(-c2ccccc2)cc1
Reaction time: 12 h

Procedure:
3.71 mmol of triethylamine and 1.8 mmol of 4-biphenylsulphonyl chloride are added at 0° C. to a solution of 1.8 mmol of the compound obtained in Step I in 15 ml of dichloromethane. The reaction mixture is brought to ambient temperature and stirred for 12 hours, and then poured into water and extracted with dichloromethane. The combined organic phases are washed with a 2N hydrochloric acid solution and then with an NaHCO3 solution, dried, filtered, and concentrated under reduced pressure. Chromatography on silica gel (dichloromethane/methanol: 20/1) allows the expected product to be isolated in the form of syrup.
Reaction SMILES: [C:1]([C:3]1[C:8]([CH3:9])=[CH:7][C:6]([CH3:10])=[CH:5][N:4]=1)#[N:2].[C:11](O)([CH3:14])([CH3:13])[CH3:12].[OH-:16].[Na+]>C(O)(=O)C.S(=O)(=O)(O)O>[CH3:12][C:11]([NH:2][C:1]([C:3]1[C:8]([CH3:9])=[CH:7][C:6]([CH3:10])=[CH:5][N:4]=1)=[O:16])([CH3:14])[CH3:13]
Reactant: [OH-]
Reactant: CC(C)(C)O
Reactant: Cc1cnc(C#N)c(C)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cnc(C(=O)NC(C)(C)C)c(C)c1
Temperature: 75 °C

Procedure:
Stir a solution of 2-cyano-3,5-dimethylpyridine (20.3 g, 0.153 mol) in 100 mL of acetic acid and 20 mL of conc. sulfuric acid over 10 minutes. Add t-butanol (20 ml.) over an additional 15 minutes. Warm the solution to 75° C. and maintain for 30 minutes. Cool to room temperature and basify with 25% NaOH. Extract the product (3X) with ethyl acetate (600 mL). Combine the organic portions and wash (1X) with brine. Dry (Na2SO4), filter and concentrate in vacuo to produce the title compound as a yellowish oil (31.26 g).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])=[N:7][C:6]=2[C:5]([C:16]#[N:17])=[C:4]([CH3:18])[C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C[N:26](C1CCC([Sn](CCCC)(CCCC)CCCC)=C1)[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30].C([C:56]1[C:61](O)=[C:60]([C:63]([CH3:66])([CH3:65])C)C=C(C)C=1)(C)(C)C>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:16]([C:5]1[C:6]2[N:7]=[C:8]([C:11](=[O:12])[N:13]([CH3:15])[CH3:14])[O:9][C:10]=2[C:2]([C:56]2[CH2:61][CH2:60][CH:63]([CH2:65][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH:66]=2)=[C:3]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:4]=1[CH3:18])#[N:17]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: Cc1c(-c2ccccc2)c(Br)c2oc(C(=O)N(C)C)nc2c1C#N
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CC(N(C)C(=O)OC(C)(C)C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: Cc1c(-c2ccccc2)c(C2=CC(CNC(=O)OC(C)(C)C)CC2)c2oc(C(=O)N(C)C)nc2c1C#N
Temperature: 100 °C
Reaction time: 24 h
Yield: 88 %

Procedure:
7-Bromo-4-cyano-N,N,5-trimethyl-6-phenyl-1,3-benzoxazole-2-carboxamide (I-339) (275 mg, 0.72 mmol) and tert-butyl methyl-(3-tri-n-butylstannylcyclopent-2-enyl)carbamate (I-332) (453 mg, 0.93 mol) were dissolved in 1,4-dioxane (8 ml), and at room temperature, 2,6-di-tert-butyl-paracresol (3 mg, 0.01 mmol) and then bis(triphenylphosphine)palladium(II) dichloride (50 mg, 0.07 mmol) were added. The solution was stirred under nitrogen atmosphere at 100° C. for 24 hours, then cooled to room temperature. The insoluble matter was separated by filtration with washing with ethyl acetate. The filtrate was concentrated under reduced pressure. The solvent was evaporated away, and the resulting residue was purified by middle-pressure liquid chromatography (eluent, n-hexane:ethyl acetate=2:1, v/v) to obtain the entitled compound (316 mg, 88%) as a colorless gel.
Reaction SMILES: [C:1]1([CH2:7][S:8](Cl)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:19])[NH:13]1.C(N(CC)CC)C>C(Cl)Cl>[CH2:7]([S:8]([N:13]1[CH:14]([C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:19])[CH2:15][CH2:16][CH2:17][NH:12]1)(=[O:10])=[O:9])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: O=C(OCCCCc1ccccc1)C1CCCNN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCCCCc1ccccc1)C1CCCNN1S(=O)(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
A solution of α-toluene sulfonyl chloride (1.12 g, 5.77 mmol) in CH2Cl2 was added to a CH2Cl2 solution containing 4-phenylbutyl perhydropyridazinecarboxylate (1.37 g, 5.2 mmol) and triethylamine (0.83 ml, 6 mmol). The reaction was stirred overnight at room temperature under nitrogen atmosphere, and then diluted to 50 ml CH2Cl2. The organic layer was washed with water, dried, and concentrated. The crude material was purified by silica gel column to yield 1.4 g (64%) final product as clear oil. Rf=0.60 (2:1 hexane:EtOAc). 1H NMR (CDCl3, 400 MHz): δ 1.68 (m, 8H); 2.67 (m, 2H); 2.90 (m, 1H); 3.38 (m, 2H); 4.22 (m, 5H); 7.32 (m, 10H). Anal. Calcd. for C22H28N2S1O4: C, 63.44; H, 6.78; N, 6.73, S, 7.70. Found: C, 63.86; H, 6.83; N, 6.41, S, 7.58.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][C:15]([CH3:19])=[C:16]([CH3:18])[N:17]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[S:14][C:15]([CH3:19])=[C:16]([CH3:18])[N:17]=1)=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: Cc1nc(N)sc1C
Product: Cc1nc(NC(=O)c2cc(Br)ccc2O)sc1C
Yield: 14.4 %

Procedure:
Using 5-bromosalicylic acid and 2-amino-4,5-dimethylthiazole as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:19][CH2:20][CH2:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1>CC#N>[CH:15]([N:4]1[C:3](=[O:18])[C:2]([NH:19][CH2:20][CH2:21][C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:5]1(=[O:14])=[O:13])([CH3:17])[CH3:16]
Reactant: CC(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: N#Cc1ccc(CCN)cc1
Solvent: CC#N
Product: CC(C)N1C(=O)C(NCCc2ccc(C#N)cc2)=C(c2ccccc2)S1(=O)=O
Temperature: 120 °C
Yield: 68.1 %

Procedure:
A mixture of 4-chloro-2-isopropyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.15 g, 0.52 mmol), 4-(2-aminoethyl)benzonitrile (0.09 g, 0.63 mmol) and TEA (0.07 g, 0.68 mmol) in MeCN (1.5 ml) was heated in a microwave reactor at 120° C. for 35 mins. 4-(2-Aminoethyl)benzonitrile (0.04 g) was added to the reaction mixture, and it was heated in a microwave reactor at 120° C. for 20 mins. The reaction mixture was evaporated and the crude product was purified by flash column chromatography using hexane and EtOAc, 80:20-50:50, as eluant, to yield the title compound (0.14 g, 67%). 1H NMR (500 MHz, CDCl3): δ 1.57 (d, 6H), 2.63 (t, 2H), 3.15-3.19 (m, 2H), 4.37-4.43 (m, 1H), 5.46 (brm, 1H), 6.86 (d, 2H), 7.45-5.55 (m, 7H); 13C NMR (125 MHz, CDCl3): δ 20.4, 36.2, 44.5, 47.9, 107.8, 111.0, 118.9, 125.2, 129.1, 129.5, 130.1, 131.8, 132.7, 135.1, 143.1, 158.6; Mass Spectrum: M−H+ 394.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][N:8]=2)[CH2:3][CH2:2]1.Br[CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=1[O:31][CH3:32].C(#N)C>O>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([CH:4]2[CH2:3][CH2:2][N:1]([CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=3[O:31][CH3:32])[CH2:6][CH2:5]2)=[N:8]1
Reactant: COc1cc(C(C)=O)ccc1OCCCCBr
Reactant: c1ccc2c(C3CCNCC3)n[nH]c2c1
Solvent: O
Solvent: CC#N
Product: COc1cc(C(C)=O)ccc1OCCCCN1CCC(c2n[nH]c3ccccc23)CC1
Yield: 78.6 %

Procedure:
A mixture of 3-(4-piperidinyl)-1H indazole (3.2 g, 0.016 mol), 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone (5.0 g, 0.016 mol) K2CO3 (2.2) and acetonitrile (100 ml) was stirred and refluxed for 6hours. The reaction was poured into water and the resulting yellow solid that formed was collected to afford 5.3 g of product. The compound was recrystallized from acetonitrile and then from ethyl acetate to yield 3.0 g (45%) of a slightly yellow solid of 1-[4-[4-[4-(1H-indazol-3-yl)-1-piperidiyl]butoxy]-3-methoxyphenyl]ethanone, m.p.=133°-135° C.
Reaction SMILES: [N+:1]([CH:3](S(C1C=CC(C)=CC=1)(=O)=O)[CH2:4][CH2:5][CH2:6][CH3:7])#[C-:2].[C:18]([O:22][CH2:23][CH3:24])(=[O:21])[CH:19]=[CH2:20].CC(C)([O-])C.[K+]>O1CCCC1.O>[CH2:4]([C:3]1[NH:1][CH:2]=[C:19]([C:18]([O:22][CH2:23][CH3:24])=[O:21])[CH:20]=1)[CH2:5][CH2:6][CH3:7]
Reactant: [C-]#[N+]C(CCCC)S(=O)(=O)c1ccc(C)cc1
Reactant: C=CC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1cc(C(=O)OCC)c[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
A solution (120 mL) of 1-[(1-isocyanopentyl)sulfonyl]-4-methylbenzene (10.8 g) and ethyl acrylate (4.78 mL) in tetrahydrofuran was added dropwise to a solution (80 mL) of potassium tert-butoxide (5.79 g) in tetrahydrofuran while stirring at room temperature over 1 hr. The mixture was further stirred at the same temperature for 30 min, and the reaction product was diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→8:2) to give the title compound as a yellow oil (yield 6.56 g, 78%).